Addressing Key Mechanisms of Tumor Drug Resistance

Transcription

1 Addressing Key Mechanisms of Tumor Drug Resistance April 2018 Kinase switch control inhibitors for tumortargeted and immune-targeted cancer therapies

2 Disclaimer This presentation has been prepared by Deciphera Pharmaceuticals, Inc. for informational purposes only and not for any other purpose. Nothing contained in this presentation is, or should be construed as, a recommendation, promise or representation Deciphera Pharmaceuticals, Inc. or any director, employee, agent, or adviser of Deciphera Pharmaceuticals, Inc. This presentation does not purport to be all-inclusive or to contain all of the information you may desire. Certain information contained in this presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and Deciphera Pharmaceuticals, Inc.'s own internal estimates and research. While Deciphera Pharmaceuticals, Inc. believes these third-party sources to be reliable as of the date of this presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. While Deciphera Pharmaceuticals, Inc. believes its internal research is reliable, such research has not been verified by any independent source. Forward-Looking Statements This presentation may contain forward-looking statements that are based on our current expectations, estimates and projections about our industry as well as management's beliefs and assumptions. Words such as "anticipates," "expects," "intends," "plans," "believes," "seeks, "estimates," "may," "will," and variations of these words or similar expressions are intended to identify forward-looking statements. These statements include statements regarding our business strategy, prospective products, clinical trial results, product approvals and regulatory pathways, timing and likelihood of success, plans and objectives of management for future operations, future results of anticipated products, and the market opportunity for our drug candidates, and speak only at the time this presentation was prepared. Such statements are based upon the information available to us now and are subject to change. We will not necessarily inform you of such changes. These statements are not guarantees of future performance and are subject to certain risks, uncertainties and assumptions that are difficult to predict. Therefore actual results could differ materially and adversely from those expressed in any forward-looking statements as a result of various factors. Factors which could cause actual results to differ materially from those in the forward-looking statements include, among others, our history of significant losses since inception, our ability to obtain necessary capital when needed on acceptable terms, the results from ongoing or future clinical and nonclinical trials, our ability to obtain regulatory approval or clearance of our drug candidates, competition from other products or procedures, our reliance on third-parties to conduct our clinical and non-clinical trials, our reliance on singlesource third-party suppliers to manufacture clinical, non-clinical and any future commercial supplies of our drug candidates and our ability to obtain, maintain and enforce our intellectual property rights for our drug candidates. This presentation may contain trade names, trademarks or service marks of other companies. Deciphera does not intend the use or display of other parties trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of, these other parties. 2

3 Corporate Summary Well established drug class with significant growth potential Differentiated approach to kinase inhibition Wholly-owned pipeline with three clinical stage assets Kinase Inhibitors: 39 FDA-approved Drugs but Significant Opportunities Remain Drug resistance mutations limit rate and duration of response Low potency and selectivity cause poor tolerability Approved drugs target less than 10% of the 500+ known human kinases Proprietary Kinase Switch Control Inhibitor Platform Broad activity against disease-initiating and drug-resistant mutant kinases Kinase-selective and spectrum-selective profiles Drug discovery engine that fuels long-term growth Strong Pipeline of Tumor-Targeted and Immunokinase Programs DCC-2618: Broad spectrum KIT and PDGFRα inhibitor in first pivotal Phase 3 trial Rebastinib: Highly potent and selective TIE2 inhibitor DCC-3014: Highly selective and potent CSF1R inhibitor 3

4 Experienced Management Team Michael D. Taylor, PhD CEO Daniel L. Flynn, PhD CSO/Founder Oliver Rosen, MD CMO Tucker Kelly, JD CFO Christopher J. Morl, MBA CBO 4

5 Strong Clinical-Stage Small Molecule Pipeline Tumor-Targeted Programs and Indications Pre-Clinical Phase 1 Phase 2 Phase 3 Global Rights Immunokinase Programs and Indications Pre-Clinical Phase 1 Phase 2 Phase 3 Global Rights DCC-2618 KIT & PDGFRα GIST 1 Rebastinib TIE2 Breast Cancer + Chemotherapy 2 PDGFRα GBM & Glioma TIE2 Checkpoint Inhibitor Combination KIT (D816V) Advanced Systemic Mastocytosis DCC-3014 CSF1R Solid Tumors & Hematological Malignancies KIT & PDGFRα Other Cancers CSF1R Checkpoint Inhibitor Combination Undisclosed Cancer Metabolism Undisclosed Immunokinase Note: (1) Phase 3 Pivotal Study in 4 th line & 4 th line+ patients. 5 Note: (2) Investigator initiated and sponsored research.

6 Our Proprietary Kinase Switch Control Platform Kinase Switched Off Kinase Switched On Deciphera Switch Control Switch pocket Activation switch Off Activation switch On Advantages of Switch Control Inhibitors Switch control inhibitor embeds deeply into switch pocket Inhibits switch activation Tumor-Targeted Programs Immunokinase Programs (Macrophage Checkpoints) Broader Activity Enhanced Durability Engineered Profiles Superior Binding Inhibit wild-type and many or all mutant forms of targeted kinases Resilient to gain-of-function mutations and drug resistance Highly selective or target multiple kinases at desired potency More potent and more durable; resilient to ATP concentration 6

7 DCC-2618: Broad Spectrum KIT & PDGFRα Inhibitor

8 DCC-2618: A Potent, Broad Spectrum KIT and PDGFRα Inhibitor DCC-2618 Summary Highly potent small molecule KIT and PDGFRα inhibitor Designed to inhibit the full spectrum of known KIT and PDGFRα mutations Fast-to-Market strategy with significant opportunity for label expansion Phase 3 pivotal trial in 4 th Line and 4 th Line+ GIST initiated January 2018 Phase 3 pivotal trial in 2 nd Line GIST planned for 2H:18 Phase 1 expansion study ongoing Clinical proof-of-concept in GIST 91% Disease Control by Best Response (PR & SD) by RECIST 100 mg daily Disease Control Rate 100 mg daily: 76% (12 weeks) and 57% (24 weeks) Favorable tolerability profile Doses up to 400 mg total per day with no MTD 150 mg QD selected for expansion and pivotal, registration Phase 3 trials IP: Composition and method of use (2032) Preclinical Profile 8

9 Pivotal Phase 3 Study in 4 th Line+ GIST Initiated Jan 2018 (1) Global Trial (n=120) 3 prior lines of therapy (1) Randomized 2:1 150 mg QD DCC Patients GIST Patients Placebo 40 Patients Primary Endpoint for Approval = Median Progression Free Survival Following progression: (a) placebo patients can crossover to DCC-2618 and (b) DCC-2618 patients can continue on treatment. Note: (1) Phase 3 Pivotal Study in 4 th line & 4 th line+ patients who previously received at least imatinib, sunitinib, and regorafenib. 9

10 GIST: A Polyclonal Disease Driven by KIT and PDGFRα Primary KIT and PDGFRα Mutations in GIST Patients Multiple Secondary KIT Mutations Produce Drug Resistance KIT and PDGFRα Mutations in GIST Wild-type tumors: 15% Primary KIT Mutations Secondary KIT Mutations KIT (75%) PDGFRα (10%) Extracellular domain Transmembrane domain Exon 9 (8%) Exon 11 (65%) Exon 13 (1%) Exon 17 (1%) Exon 12 (2%) Exon 14 (rare) Exon 18 (8%) (Includes D842V) Juxtamembrane domain Tyrosine kinase domain I/ ATP-binding pocket Tyrosine kinase domain I/ ATP-binding pocket Corless; M. Pathology 2014 George; Ther. Adv. in Medical Oncology

11 Multiple Drug-Resistant Secondary Mutations in GIST Drug-Resistant Secondary KIT Mutations in GIST Patients Span Exon Regions Distribution of secondary KIT mutations (n=27) Fletcher; J. Pathol 2008 Switch Pocket Region Switch Region A I H G Y Y K D P V Exon 13 Exon 14 Exon 17 Exon 1 8 ATP binding pocket 42.9% T Kinase activation loop 57.1% Color code for primary mutation D D D N N Y Exon 11 Exon 9 Exon 13 A High Degree of Tumor Mutation Heterogeneity in GIST Patients Number of secondary mutants detected per patient 10 (n=37)* Number of Secondary Mutants per Patient secondary mutations were observed in 35% (13/37) of patients. 54% (13/24) of patients with KIT exon 11, with 1 patient harboring 8. Heinrich, Abstract ASCO 2015 Primary Mutation Status KIT exon 11 KIT other** KIT WT 11 Notes: (*) Number of unique secondary mutants per patient observed across all samples analyzed; (**) Includes exon 9 (n=6), exon 13 (n=1), and exon 17 (n=1).

12 DCC-2618 Broad Coverage of Primary and Secondary Mutations in KIT and PDGFRα DCC-2618 Broadly Inhibits KIT and PDGFRα Mutations In Enzyme Assays DCC-2618 Inhibits Phosphorylation of KIT and PDGFRα in Cellular Assays K inase Inhibition at 1 m M A TP DCC-2618 (Type II) DP-5439 (Type II) Im atinib (Type II) S unitinib b (Type II) Regorafenib (Type II) Midostaurin (Type I) BLU-285 (Type I) IC 50 (nm ) K IT a V654A T670I D816H D816V PDGFRA D842V KIT a V654A T670I D816H D816V PDGFRA D842V K IT a V A T I D816H D V DCC-2618 broadly inhibits KIT mutations in exons 9, 11, 13, 14, 17, 18, and a PDGFRA exon 18 mutant. Other Type II inhibitors do not block KIT exon 17 mutations, including D816V KIT. Type I inhibitors exhibit weak activity for primary KIT mutations in exon 9, exon 11 V560D, and exon 13 K642E and for secondary KIT mutations in exons 13 and 14. PDGFRA D842V KIT a V A T I D H D V P D G F R A D V K IT a V A T I D H D V P D G F R A D V K IT a V A T I D H D V P D G F R A D V K IT a V A T I D H D V a Phosphorylated on the juxtamembrane domain. b Sunitinib is Type I-like but binds to KIT in the inactive Type II conformation. P D G F R A D V Mutation Exon KIT V654A 13 KIT T670I 14 KIT D816H 17 KIT D816V 17 PDGFRA D842V Notes: (A) GIST primary mutations; or imatinib-resistant KIT mutations with (B) exon 9 or (C) exon 11 primary mutations.

13 Approved Therapies for GIST: Clinical Goal is Disease Control First Line Second Line Third Line imatinib (n=147) (Blanke et al. 2008) sunitinib (n=243) (Demetri et al. 2012) regorafenib (n=133) (Demetri et al. 2013) Progression Free Survival 1 (months) Objective Response Rate (%) 68.1% 7.0% 4.5% Stable Disease (%) 15.6% 53.0% 48.1% Disease Control Rate ( DCR ) (%) 83.7% % % 3 No approved therapy for 4 th line patients Notes: (1) Includes progression free survival and time to progression; (2) Time point not disclosed; (3) Time point at 12 weeks. 13

14 DCC-2618 Phase 1 Trial Part 1: Dose Escalation Key Objectives: MTD, recommended Phase 2 dose, safety, tolerability, pharmacokinetics and anti-tumor activity Design: 3+3 design with enrichment of targeted patients Dose Levels: 20, 30, 50, 100, 150, and 200 mg BID; and 100 and 150 mg QD MTD: not determined Part 2: Dose Expansion 6 cohorts enrolling (up to 200 patients) 4 th Line GIST 5 th Line GIST 2 nd 3 rd Line GIST Advanced Malignancies (n=68) Recommended Dose 150 mg QD Phase 1 Trial Enrollment as of January 18, total patients ( mg QD) 142 GIST patients (100 GIST 150 mg QD) Systemic Mastocytosis and Associated Hematological Malignancies Malignant Gliomas Other Solid Tumors 14

15 Broad and Sustained Tumor Control in GIST Patients 91% Disease Control (PR & SD) at Best Response by RECIST at 100 mg Daily Best Response per RECIST KIT & PDGFRα All Doses (n=37) 76% DCR 100 mg Daily (12 Weeks) 57% DCR 100 mg Daily (24 Weeks) Tumor Control per RECIST KIT & PDGFRα 100 mg Daily (n=33) # # # # # # # # # * Notes: (a) Uncleaned EDC data per investigator assessment; (b) Includes only KIT and PDGFRα GIST patients; excludes one SDH GIST patient (c) PD = Progressive disease, SD = Stable disease, PR = Partial response (d) *Indicates a 66% increase in tumor size; (e) # = 150mg QD; (f) per investigator assessment. Notes: (a) Closed circles denote patient on DCC-2618 at time of scan; (b) Open circles denote patient was off DCC-2618 at time of scan; (c) Stars indicate final visit; (d) per investigator assessment. (e) Patient #13 censored (week 24) due to surgery; on study (week 53) as of cut off. 15

16 Clinical Validation of The Broad Spectrum Profile in Liquid Biopsies Reductions in Circulating MAF of Mutations in all Clinical Relevant Exons (n=19) (Note log scale: -1 = 10-fold reduction, -2 = 100-fold reduction) fold + 10 fold # # - 10 fold fold - 1,000 fold 47 Ex 9 Ex 11 Ex 13 Ex 14 Ex 17 Ex 18 KIT mutations across 6 exons (9, 11, 13, 14, 17 & 18) Notes: (a) Patient #3 in first dose cohort; (b) Patient #*34 presented with mixed histology; (c) 47 KIT mutations based on data from 27 patients including 8 with only baseline data. 16

17 Duration of Treatment in Heavily Pretreated GIST Patients (n=57) (a)(b) Median PFS with placebo in 3 rd /4 th line (<1 month) AACR 2018 Update (c) GIST pts 100 mg/d as of 1/18/18 (n=137): 81 of 137 remain on study as of 3/19/18 >6 months on study (n=46) >9 months on study (n=21) >12 months on study (n=10) >15 months on study (n=7) Notes: (a) Tumor response data is based on investigator assessment; (b) Data from presentation at ESMO on September 11, 2017; (c) Data from presentation at AACR on April 15, Weeks on DCC = patients receiving 150mg QD

18 Early Progression Free Survival Data Progression-Free Survival Rate KIT- and PDGFRα-driven GIST Patients 100 mg daily (n=49) vs. < 100 mg daily (n=4) Median PFS with placebo in 3 rd /4 th line (<1 month) Progression-free survival mpfs is 15.2 weeks (CI 4.4 to 24) All patients treated at <100mg daily (n=4) mpfs cannot be determined All patients treated at 100mg daily (n=49) Notes: (a) Circles are patients (potentially >1 at any time point) who had not progressed as of end of treatment/study or last visit date if still on treatment; (b) Data is based on tumor response data investigator assessment. 18

19 Activity in GBM with a Durable Partial Response Society for Neuro-Oncology (November 2017) Baseline Post Cycle 22 Baseline 51.4 mm x 26.8 mm Cycle 23 Day mm x 8.4 mm 1 PR of 4 Evaluable GBM Patients 3 Patients Non-evaluable at Cut-off (1 PD, 2 Active) Stage 4 GBM with PDGFRα, KIT, VEGFR2 6x amp. 94% Tumor Reduction per RANO after 22 Cycles 19

20 Favorable Tolerability Profile Treatment-emergent Adverse Events in (10%) GIST Patients 150 mg QD Phase 1 Dose Escalation (n=68) Well tolerated up to 400 mg per day MTD not reached 3 DLTs: Reversible plasma enzyme elevations: lipase (2) and CPK (1) Deemed not clinically significant 150 mg QD dose for Phase 1 Expansion and 4 th Line GIST Phase 3 Trial GIST 150 mg QD ADVERSE EVENT GRADE GRADE TOTAL 1/2 3/4 (n=100) Alopecia (39%) Fatigue (39%) Myalgia (35%) Constipation (29%) Hand-Foot-Skin reaction (27%) Rash (21%) Lipase increased (20%) Nausea (19%) Decreased appetite (18%) Diarrhea (18%) Hypertension (17%) Abdominal pain (16%) Arthralgia (15%) Weight decreased (13%) Headache (12%) Vomiting (12%) Anemia (11%) Dyspnea (11%) Hypomagnesaemia (11%) Pain in extremity (11%) Dry skin (10%) Muscle spasms (10%) 20

21 Estimated Market Opportunity: US, EU & Japan Incidence Metastatic GIST US EU Japan Total (exc. ROW) KIT-driven 4 th Line 1&2 ~2,100 ~3,300 ~800 ~6,200 KIT-driven 2 nd Line 1&2 ~2,600 ~4,000 ~1,000 ~7,600 PDGFRα-driven 1&2 ~400 ~600 ~160 ~1,160 GBM & Glioma (PDGFRα Amp.) 3&4 ~2,400 ~3,700 ~900 ~7,000 Advanced Systemic Mastocytosis 5 ~1,400 ~2,100 ~500 ~4,000 Estimated Annual Incidence of New Patients by Indication Sources: Internal Deciphera estimates based on applying epidemiology data reported in the following publications to population estimates for US, EU (28) and Japan: 1 Zhao et al. J Gastrointest Oncol 2012;3(3): Metaxas Y, et al. ESMO Open Bastien et al.cancer 2014;121: Schwartzbaum et al. Nature Clinical Practice Neurology Sep 2006 Vol 2 No 9 5 Cohen et al. British Journal of Haematology, 2014, 166,

22 Immunokinase Programs Targeting Macrophage Checkpoints: Rebastinib and DCC-3014

23 Immunokinase Programs: Rebastinib and DCC-3014 Combining T-Cell and Macrophage Checkpoint Inhibitors Targeting T-Cells and Macrophages to Produce Strong Tumor Cell Killing 23

24 Rebastinib: A Highly Potent and Selective TIE2 Inhibitor TIE2 Legend: IC50= 10 nm IC50 = 1 nm Rebastinib Summary Potent, small molecule inhibitor of TIE2 Phase 1 study completed Patients with relapsed/refractory chronic (BCR-ABL+) or AML (FLT3-ITD) MTD determined based on targeting BCR-ABL. 100x more potent inhibitor of TIE2. Lower dosing to be used for future development. Preclinical anti-tumor activity Single agent and I/O or chemo combination TIE2 microenvironment mechanisms Tumor vascularization, dissemination, metastasis, immunotolerance Development Status Ongoing investigator-sponsored chemo combo trial Company sponsored combination trial planned for 2018 IC50 = 0.1 nm IP: Composition (2027) and method of use (2034) Kinome Profile 24 Notes: All kinases within 100-fold of TIE2 IC50 (0.058 nm) are shown. Includes enzyme data at low ATP and 4 mm ATP, and cellular data

25 Rebastinib: Rationale for Use in Combination Therapies Rebastinib Inhibits Growth of Breast Tumors (PyMT) Alone and in Combination With Paclitaxel Rebastinib Inhibits Growth of Breast Tumors (PyMT) Alone and in Combination With PD-1 PyMT Mean Primary Tumor Burden PyMT 3000 Mean Tumor Burden (mg) +/- SE PyM T M ean Prim ary Tum or Burden Days Post Tumor Implant V ehicle Paclitaxel 10 mg/kg Q5Dx5 IV Rebastinib 10 mg/kg BID PO Rebastinib + Paclitaxel Paclitaxel 49% TGI R eb a stin ib 75% TGI Rebastinib plus Paclitaxel 90% TGI Tumor volume (mm 3 ) Day Notes: *TGI normalized to starting tumor size: Paclitaxel (49%TGI*) Rebastinib (75%TGI*); Rebastinib plus Paclitaxel (90%TGI*). Anti-PD1 (RMP1-14) 10 mg/kg IP BIW Rebastinib + Anti-PD1 Vehicle Rebastinib 10 mg/kg PO QD 25

26 DCC-3014: A Highly Selective and Potent CSF1R Inhibitor DCC-3014 Summary Highly selective, potent, small molecule CSF1R inhibitor 100x selectivity over closest kinases Phase 1 study ongoing Up to 55 patients with advanced malignancies (including solid or hematological malignancies where TAMs may be involved) Preclinical anti-tumor activity Single agent and in combination with anti-pd1 CSF1R mechanisms Reverses immunosuppression via depletion of TAMs, increases in cytotoxic T cells and decreases in T reg cells Development Status Phase 1 trial ongoing 4mM ATP Legend: 10 μm 1 μm 100 nm 10 nm 1 nm IP: Composition and method of use (2034) Kinome Profile 26

27 DCC-3014: Rationale for Combination with PD-1 Inhibitors DCC-3014 Inhibits Growth of Colorectal Tumors Alone and in Combination with anti-pd-1 DCC-3014 Reverses Immunosuppression in Colorectal Tumor Model MC-38 Primary Tumor Growth Decrease in ratio of TAMs to CD8 cytotoxic T Cells Increase in ratio of CD8 cytotoxic T Cells to T reg cells Macrophage:CD8+ T cell Ratio MC-38 Syngeneic Model Tumor Flow Cytometry Analysis Ve hicle DCC mg/kg Cytotoxic CD8+ T cell:treg Ratio MC-38 Syngeneic Model Tumor Flow Cytometry Analysis Ve hicle DCC mg/kg 27

28 Upcoming Milestones AACR: Phase 1 Escalation Data 4 th line GIST: Pivotal Phase 3 Initiated 4 th Line GIST: Pivotal Phase 3 Initial Data DCC-2618 Phase 1 Expansion Initiation ASCO: Phase 1 Escalation Data Phase 1 Dose Escalation Completion AACR: Phase 1 Safety/PK Data AACR: Preclinical Data Phase 1 Safety & Efficacy Data Phase 1 Expansion Data ESMO: Phase 1 Escalation Data SNO: Phase 1 Glioma Data 2 nd line GIST: Pivotal Phase 3 Initiation DCC-3014 Phase 1 Dose Escalation Initiation Phase 1 Dose Escalation Initial Data Rebastinib AACR & ASCO: Trial-in-Progress posters (Investigator sponsored) AACR: Initial Phase 1b Data (Investigator sponsored) Phase 1b Combination Initiation (Company sponsored) Phase 1b Combination with I/O or Chemotherapy Data (Company sponsored) 28

29 NASDAQ:DCPH Shares Outstanding (as of 12/31/17) Cash & Cash Equivalents (as of 12/31/17) 32.6 MM (basic) 37.2 MM (fully-diluted) $197MM Cash to fund operating expenses and capital expenditures into 2H

30 Corporate Summary Well established drug class with significant growth potential Differentiated approach to kinase inhibition Wholly-owned pipeline with three clinical stage assets Kinase Inhibitors: 39 FDA-approved Drugs but Significant Opportunities Remain Drug resistance mutations limit rate and duration of response Low potency and selectivity cause poor tolerability Approved drugs target less than 10% of the 500+ known human kinases Proprietary Kinase Switch Control Inhibitor Platform Broad activity against disease-initiating and drug-resistant mutant kinases Kinase-selective and spectrum-selective profiles Drug discovery engine that fuels long-term growth Strong Pipeline of Tumor-Targeted and Immunokinase Programs DCC-2618: Broad spectrum KIT and PDGFRα inhibitor in first pivotal Phase 3 trial Rebastinib: Highly potent and selective TIE2 inhibitor DCC-3014: Highly selective and potent CSF1R inhibitor 30

31 Addressing Key Mechanisms of Tumor Drug Resistance April 2018 Thank You